Brachyury (also known as “T”) was identified in mice as a dominant short tail mutant that is also a recessive lethal; homozygous T/T embryos die in mid-gestation due to a failure of posterior mesoderm formation (Chesley, J. Exp. Zool., 70: 429-459, 1935). The murine Brachyury gene has been cloned (Herrmann et al., Nature (Lond.), 343: 617-622, 1990), as well as the homologs in other species, such as humans. The expression of the human homologue of the mouse Brachyury was detected by RT-PCR in the notochord remnant, the nucleus pulposus, of human abortuses at 14-15 weeks gestation (Edwards et al., Genome Res., 6: 226-233, 1996).
Brachyury has generally proved a valuable marker for recognition of mesodermal differentiation (Herrmann et al., Trends Genet., 10: 280-286, 1994). For example, apart from expression in embryos themselves, Brachyury has been reported to be activated during the differentiation of certain murine EC and ES cell lines differentiating along mesodermal lineages in vitro (see, for example, Bain et al., Biochem. Biophys. Res. Commun., 223: 691-694, 1996). In humans, Brachyury has been shown to be expressed in teratocarcinomas (Gokhele et al., Cell Growth and Differentiation 11:157-62, 2000), chordomas (Vujovic et al., J. Pathol. 2: 157-65, 2006) and hemagioblastomas (Glasker et al., Cancer Res. 66: 4167-4172, 2006).
Immunotherapy involves evoking an immune response against cancer cells based on their production of target antigens. Immunotherapy based on cell-mediated immune responses involves generating a cell-mediated response to cells that produce particular antigenic determinants, while immunotherapy based on humoral immune responses involves generating specific antibodies to cells that produce particular antigenic determinants.
Recent studies show that immunotherapy of cancer patients may be dramatically improved by the finding that CD8+ CTLs recognize and kill tumor cells that display peptides from tumor-associated antigens within MHC Class I molecules. In clinical studies it has been found that effector CD8+ T cells play a major role in tumor regression. For example, several tumor antigens in prostate cancer models have been identified and HLA allele-specific peptides from those prostate cancer-associated antigens have been identified as CD8+ T cell epitopes. For example, HLA-A2.1 binding peptides were described that were derived from prostate specific antigen (PSA) (Correale et al., J Immunol 161:3186, 1998), prostate-specific membrane antigen (PSMA) (Tjoa et al., Prostate 28:65, 1996), prostate stem cell antigen (PSCA) (Kiessling et al., Intl Cancer 102:390, 2002), and prostate acid phosphatase (Peshwa et al., Prostate 36:129, 1998). For PSA, clinical trials are in progress using different vaccine strategies. However, there clearly is a need to identify additional antigens to aid in the diagnosis of cancers of different organs, and to produce peptides that can be used for immunotherapy of other types of cancer.